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Posts Tagged ‘Development’

Noradrenergic relief of problematic impulses can be seen through the slit(rk1)

Posted in ADRA2A, Locus coeruleus, Noradrenaline, SLITRK1, tagged , , , , , on January 9, 2009| Leave a Comment »

Clonidine
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A recent report by Katayama and colleagues [doi 10.1038/mp.2008.97] shows that the the gene slitrk1 – a known risk factor for the developmental disorders  Tourette’s syndrome and trichotillomania gives rise to increased levels of noradrenaline when the gene is inactivated in a developing mouse model.  In the U. S., the most frequently prescribed medications for these disorders are clonidine hydrochloride (Catapres®) and guanfacine (Tenex®), which inhibit the synaptic transmission from presynaptic nerve terminals that express the alpha 2-adrenergic receptor.  Thus, the mouse model (mice with the inactive slitrk1 gene were healthy but showed behavioral abnormalities that were normalized upon treatment with clonidine) seems to validate the current form of treatment since a reduction in noradrenergic release, might counteract the higher levels of noradrenaline associated with the risk-promoting slitrk1 mutation.

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Dendritic branching a good thing ? sez6 sez it ain’t so

Posted in SEZ6, tagged , , , , , , , on January 7, 2009| Leave a Comment »

Drawing of Purkinje cells (A) and granule cell...
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If you like gardening, the doldrums of winter can be dreary indeed. Although I’d never admit to it, my neighbors might swear to having seen me outside strangely (pathetically) counting the number of branches on my icicle-laden roses and rhododendrons.  In any case, I do admit to spending way too much time forlornly staring at my garden from the window while fantasizing about all the things I’ll plant come springtime.

Each new branch brings a new burst of color and fragrance and concomitant joy.  A good thing right ?  Similarly, each neuron in the brain – which look just like little trees with branches – should also strive to send out as many new branches and make new synaptic connections.  Afterall, there are brain disorders associated with a loss of or fewer dendrites, such as Down’s syndrome and schizophrenia. More branches, more synapses, more brain power and concomitant joy ? Well, perhaps not quite.

A gene known as seizure-related gene 6 (sez6) which is expressed in the developing brain as well as in response to environmental stimulation, seems to play a role in limiting the the number of branches that a neuron can send out.  Gunnersen and colleagues [doi: 10.1016/j.neuron.2007.09.018] show that mice that carry an inactivated version of sez6 show more dendritic branches (implying that the normal function of the active gene is to inhibit branch formation), and that this is definitely not a good thing.  These sez6(-/-) mice, while looking rather indistinguishable from their normal littermates, did not perform as well on tasks involving motor control, memory and emotional sensitivity (implying that having too many branches may not be so beneficial).  In humans, a frameshift mutation involving an insertion of a C residue at position 1435 of the cDNA is associated with febrile seizures, similarly suggesting that dendritic overload can have negative effects on human brain function.

Clearly, the human brain seeks a balance between too many and too few dendritic branches.  I suppose most experienced gardeners would also agree that too many branches is not desirable.  Perhaps they are right.  However, I don’t think I’d mind much if plants came with an analogous sez6 mutation !

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How genes can contribute to hypersocial behavior

Posted in Collateral sulcus, Fusiform gyrus, LIMK1, Parahippocampal gyrus, tagged , , , on December 19, 2008| Leave a Comment »

The visual dorsal stream (green) and ventral s...
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One of the longstanding puzzles of brain development is why, in some cases, individuals with developmental disabilities sometimes show enhanced function, rather than a more typical loss of cognitive function.  In the case of Williams Syndrome – which is caused by a hemizygous deletion of a cluster of about 25 genes on 7q11.23 – children show a mild form of mental retardation but also a notable increase in gregarious and social behavior.  How might a genetic deletion lead to a gain of function ? In a recent paper by Sarpal and colleagues [doi:10.1093/cercor/bhn004], they explore the role of the visual cortex and its role in feeding and filtering information to emotional  regions of the brain.

From its receipt of visual information from the eyes – say perhaps, you’re looking at someone’s face, the primary visual cortex parses information into 2 separate streams – a dorsal stream which is good at processing “where” information related to location; and a ventral stream which is good at processing “what”information related to identity and recognition – and moreover, provides inputs to the prefrontal and amygdala (brain regions which are important for social behaviors). What if the genes deleted in Williams Syndrome altered the development of a part of visual cortex that participates in early visual processing to alter the relative balance of dorsal to ventral processing ?  Might it result in a an individual who was better than usual at processing objects (faces) and also showing related emotional traits ? Indeed, this has been a longstanding hypothesis that has since been supported by findings that show relatively intact ventral stream processing but disrupted dorsal stream processing.

In their current paper, Sarpal and colleagues measured brain activity as well as correlations of activity (connectivity) between brain regions as patients with WS passively viewed visual objects (faces and houses).  They report that connections from early visual processing areas (fusiform and parahippocampal gyrus) in WS are actually weaker to the frontal cortex and amygdala.  Since activation of the frontal cortex and amygdala are associated with inhibition and fear, it may be case that the weaker connections from early visual areas to these regions gives rise to the type of gregarious and prosocial (a lack of fear and inhibition) behavior seen in WS.   In further pinpointing where in the brain the genes for WS might be causing a developmental change, the authors point to the ventral lip of the collateral sulcus, an area situated between the fusiform and parahippocampal gyri.  This may be the spot to more closely examine the role of genes such as LIMK1 – a gene that participates in the function of the actin cytoskeleton (an important process in synaptic formation).

This lecture by V.S. Ramachandran covers some of these pathways with respect to Capgras Syndrome.

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Cock-a-doodle-don’t from chicks with quail neural transplants

Posted in acetylcholine, Neural crest, Noradrenaline, tagged on November 17, 2008| Leave a Comment »

California Quail

Image by Len Blumin via Flickr

Am just working up a review on the genetic regulation of the noradrenergic system and stumbled across a collection of papers from ye olde 1980’s. A scientist named Nicole Le Douarin has a series of papers performing a surgical switcheroo of neural tube & neural crest cells from the quail into the chick.  Apparently, the cells survive and differentiate into mature structures and (because the quail cells were distinguishable by Feulgen stain) were a great way to study the effects of “genes vs. environment” on the development of specific cell types. Noradrenergic cells, it turns out can be induced to express cholinergic proteins in response to external cues for example. Interestingly, the chicks born with quail transplants crowed like quail, rather than chicks, demonstrating “the first demonstration of cross-species behavioral transfer brought about by neuronal transplantation.” Balaban et al., Science magazine (1988) vol 241, page 1339.

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“sintinaptoo” is a nonword that makes it hard to read nonwords

Posted in CNTNAP2, FOXP2, Myelin, Superior temporal cortex, tagged , , , , on November 7, 2008| Leave a Comment »

Day 191 - Stick it Out

Image by lintmachine via Flickr

Like “Joe the Plumber” (whose real name is Samuel), CNTNAP2 (whose real name is CASPR2) has achieved a bit of fame lately.  While recently appearing almost everywhere (here, here, here) except FOX News, CNTNAP2 (not Joe the Plumber) is apparently a transcriptional target of the infamous FOXP2 “language gene” – so says Sonja C. Vernes & colleagues [doi: 10.1056/NEJMoa0802828] who precipitated DNA-protein complexes using anti-FOXP2 antibodies from a cell line transiently expressing FOXP2. The team later evaluated measures of expressive and receptive language abilities and nonsense-word repetition and found that a series of snps – most significantly rs17236239 – were associated with performance of children from a consortium of families at risk for language impairment.  This adds to several previous reports of CNTNAP2 and risk for autism, a disorder where language ability is severely impaired.

So what’s all the fuss ? How can something so insignificant (rs17236239 not Joe the Plumber) stir up so much trouble ?  Well, as reported in a previous post, the expression of CNTNAP2 in the developing superior temporal cortex may be a relevant clue since this brain region is activated by language tasks.  Also, this gene encodes a rather massive protein which (as reported by Coman et al.,) seems to participate in the establishment of myelination and “nodes” that permit rapid neural transmission and long-range coordination across neural structures in the brain. Interestingly, this gene shows evidence for recent positive selection in humans (as posted on here and here) although the newly derived G-allele at rs17236239 seems to be the allele that is causing the language difficulties.  My own 23andMe profile shows a middling A/G here which makes it slightly hard to recall and repeat “Samuel Wurzelbacher”.

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Fat gene demonstrates role in cognitive development

Posted in Leptin, tagged on July 22, 2008| Leave a Comment »

Bowl of Image via Wikipedia Sometimes we humans tend to think we’re pretty sophisticated, but let’s face it, once we’ve got a fridge full of food and a partner to mate with, most of us – like every other species – are pretty content. So it may seem reasonable, from an evolutionary standpoint, that a gene that regulates food intake and metabolism – leptin – would have wide-ranging effects on almost every physiological system in the human body including: immune, reproduction, endocrine, skeletal and CNS. A new PLoS ONE paper entitled, “Leptin Replacement Improves Cognitive Development” reports that administration of recombinant leptin to a 5-year-old boy with a nonconservative missense leptin gene mutation (Cys-to-Thr in codon 105) yields dramatic improvements in neurocognitive function. The open access paper describes the many known effects on leptin on neuronal plasticity and it is wonderful indeed to see its success when used as a therapeutic agent. That the development of so-called ‘higher’ cognitive function in humans is regulated by a small peptide secreted by fat cells may be an affront to some, but not me. “Honey, pass the chicken wings !”

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rs1344706 gives tenuous clue to cerebellar involvement in schizophrenia

Posted in ATXN1, Cerebellum, ZNF804A, tagged , on May 7, 2008| Leave a Comment »

Ataxin 1Image via Wikipedia The recent SNP association report, “Identification of loci associated with schizophrenia by genomewide association and follow-up“ (doi:10.1038/ng.201) by O’Donovan et. al, – an analysis of more than 370,000 Affymetrix SNPs on a population of 479 affected individuals – finds strong evidence for c in the zinc finger protein 804A (ZNF804A). One clue to the otherwise inscrutable history of this gene may lie in the findings of a yeast 2-hybrid screen where ataxin-1 was used as a bait. Mutations in ATXN1 can give rise to Spinocerebellar Ataxia, a degenerative condition of the cerebellum and spinal cord. Such profound developmental deficits, even if weakly expressed would be consistent with the many cognitive difficulties experienced by patients with schizophrenia.

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Genetic regulation of cortical structure in the pediatric brain demonstrated by landmark twin study

Posted in Frontal cortex, Middle temporal gyrus, Supramarginal gyrus, tagged , , on April 28, 2008| Leave a Comment »

PhotoImage via Wikipedia Like most parents, I enjoy watching my children develop and marvel at the many similarities they bear to myself and my wife. The reshuffling of physical and behavioral features is always a topic of discussion and is the definitive icebreaker during uncomfortable silences with the inlaws. In some cases, the children are blessed with the better traits, but in other cases, there’s no option but to cringe when, “Look – wow, he really has your nose – hmmm”, is muttered. Most interesting, is the unfolding of patterns of behavior that unfold slowly with age. Differences in temperament and personality can instill great pride in parents but also can be a grating source of friction. One of my F1’s has recently taken to sessions of shrill, spine rattling, screaming which I hope will pass soon.

Why ? Many parents ask. “Have WE been raising him/her to do this ? – surely that’s what the neighbors must think”. “Is it something in the family ? I heard Aunt Marie was a bit of a screamer as a child – hmmm.”

In one of several of their landmark studies on the genetic regulation of pediatric brain development, Jay Giedd and colleagues, now provide in their recent paper, “Variance Decomposition of MRI-Based Covariance Maps Using Genetically-Informative Samples and Structural Equation Modeling”, a core framework on the relative contribution of genes vs. environment for the developing cortex. The paper is part of an ongoing longitudinal study of pediatric brain development at the Child Psychiatry branch at NIMH. Some 600 children participated – including identical twins, fraternal twins, siblings and singleton children.

The team used an analytical approach known as MACAAC (Mapping Anatomical Correlations Across the Cerebral Cortex) to ask how much does the variation in a single part of the brain co-vary with other parts ? Then the team used structural equation modeling to explore how much this co-variation might differ across identical twins vs. fraternal vs. siblings vs. age-matched singleton children. In locations where there is an high genetic contribution to co-variation in cortical thickness, identical twins should co-vary more tightly than fraternal twins or siblings etc. In this way, the team were able to parse out the relative influence of genes vs. environment to the developing brain.

In general terms, the team reports that a single genetic factor accounts for the majority of variation in cortical thickness, which they note may be consistent with a major mechanism of development of cortical layers involving the migration of neurons along radial glia. Genetic co-variances across separate locations in the brain were highest in the frontal cortex, middle temporal gyrus and left supramarginal gyrus. Interestingly, when environmental covariations were observed, they were usually restricted to just one hemisphere, while genetic covariations were often observed bilaterally.

Figure 5 of this paper is really incredible, it shows which areas of the cortex are more influenced by genes vs. environment. If I can just find the areas involved in screaming, the next time one of my neighbors looks askance at my F1, I’ll be able to explain.

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Foxa2 (+/-) trapped as first true model for Parkinson disease

Posted in Dopamine, FOXA2, tagged , , on December 28, 2007| Leave a Comment »

Fred Sanford
Image by Thomas Hawk via Flickr

Mouse models of complex neurological illness are a powerful means to dissect molecular pathways and treatment paradigms. Current mouse models for the tremors and movement difficulties seen in Parkinson disease include genes such as parkin, alpha-synuclein, LRRK2, PINK1 and DJ-1. These models however, do not show the motor control problems and spontaneous degeneration of dopamine neurons as seen in PD in human patients. A new mouse model as reported by Kittappa and colleagues, unlike previous models, does, however, show amazing verisimilitude to PD. In their paper, “The foxa2 Gene Controls the Birth and Spontaneous Degeneration of Dopamine Neurons in Old Age” (DOI) the authors find that mice with only a single copy of the foxa2 gene acquire motor deficits and a late-onset degeneration of dopamine neurons. The age-related spontaneous cell death preferentially affects dopamine producing neurons in the substantia nigra that are affected in PD. The link between genetic risk and environmental exposure to oxidative toxins, a known risk factor in PD, is remarkably straightforward as foxa2 appears to be a regulator of superoxide dismutase, a potent protective scavenger of damage-inducing free radicals. More amazingly still, the authors demonstrate that foxa2 plays a key role in the birth of dopamine neurons – thus opening up new therapeutic possibilities of simultaneously producing new neurons and blocking apoptotic death of old ones. This fox brings new hope for treatment !

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Carving the cognitive turkey at the genetic joints

Posted in Uncategorized, tagged , , , on December 11, 2007| Leave a Comment »

Brad carves the turkey
Image by Salim Virji via Flickr

It has long been known that complex neuropsychiatric and neurodevelopmental illnesses have familial patterns of inheritance and that concordance in identical twins is greater than in fraternal twins. The genetic influences of mental illness – whilst apparent – do not, however, provide clues about which genes, of the 20,000 or so to choose from, confer risk. Hallucinations, mania, mood-swings, paranoia, disorganized thinking – to describe some of the difficulties that patients experience – do not immediately suggest specific candidate molecules. In an effort then, to pinpoint the specific neural processes that go awry in one particular complex mental illness, the The Consortium on the Genetics of Schizophrenia has published a landmark analysis of 183 nuclear families consisting of affected and unaffected siblings to address this problem. In their paper, “Initial Heritability Analyses of Endophenotypic Measures for Schizophrenia” (Arch Gen Psychiatry. 2007;64(11):1242-1250) the team examine so-called endophenotypes, often consisting of cognitive assessments designed to engage discrete, anatomically characterized neural networks in order to zero-in on where in the brain the genetic risk exerts an effect. The critical point the authors make is that these endophenotypes must be shown to be reliable, stable, and, most importantly, heritable. In other words, while many neural proceeses may go awry in schizophrenia, not all of these processes will have been influenced by genetic factors. Hence the analogy to carving up the complex system (turkey) along the proper genetic lines (joints). Their analysis showed that a great many of their candidate endophenotypes are indeed heritable, such as pre-pulse inhibition of the startle response, the antisaccade task for eye movements, Continuous Performance Test, California Verbal Learning Test, Letter-Number Sequencing test, Abstraction and Mental Flexibility, Face Memory, Spatial Memory, Spatial Processing, Sensorimotor Dexterity, and Emotion Recognition. Other processes such as suppression of the P50 ERP was not found to be heritable, and thus may not be a process that is affected by genetic risk. Interestingly, as reported by the authors, “The genetic correlations observed between the CVLT and LNS, between Abstraction and Mental Flexibility and Spatial Memory, and between Spatial Processing and the antisaccade task, CPT, LNS, and Abstraction and Mental Flexibility were significant at the P .001 level and remained significant after correction for multiple testing. These results suggest that overlapping genetic architecture (pleiotropy) underlies some of these endophenotypes”. Further dissection of these validated endophenotypes may therefore yield more specific neural processes, and perhaps specific synaptic connections, that would more readily provide clues to the molecular players in these complex developmental disabilities.

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Genes for language development and autism are expressed right where they should be

Posted in CNTNAP2, LDB1, Superior temporal cortex, tagged , , on December 7, 2007| 1 Comment »

raining words; in a moment
Image by pfv. via Flickr

The acquisition of language in humans remains a complex and fascinating mystery from both a neuro- and evolutionary-biological perspective. Attempts to identify genetic regulators of neural processes that are involved in language acquisition have the potential to shed light, not only on the natural history of homo sapiens, but also, to help understand the complex neurodevelopmental disorder, Autism, often associated with profound language impairments. So, it is very exciting to read, “Genome-wide analyses of human perisylvian cerebral cortical patterning” by Abrahams et al., (DOI) who examined human gene expression in frontal vs. superior temporal cortex at a developmental period where neurogenesis and neuronal migration are particularly active. The authors went looking for differential gene expression during a critical developmental time point and in a critical brain region – since the superior temporal cortex is an area that is reliably activated by linguistic tasks as well as social cognition tasks. According to the article, a total of 345 differentially expressed genes were identified, with 61 enriched and 284 down-regulated in superior temporal cortex across two microarray platforms, with 13 genes identified by both microarray array platforms. One of the genes identified is LDB1, a regulator of the asymmetrically expressed LIM domain-only 4 (LMO4) a known mediator of calcium-dependent transcription in cortical neurons and known to regulate thalamocortical connectivity. Another gene, CNTNAP2, a member of the neurexin transmembrane superfamily of proteins that mediate cellular interactions in the nervous system has been previously associated with autism. Both of these genes seem to have important developmental roles and should provide access to the fine-scale wiring that occurs during the development of neural networks involved in language.

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“Having intelligence may have its limitations, but a thin corpus callosum is not thus handicapped.”

Posted in Corpus callosum, White matter, tagged , on September 21, 2007| Leave a Comment »

James Watson (February, 2003)
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For geezers who may recall the 1994 furor over The Bell Curve, research on genetics and intelligence has a Paris-Lindsay-&-Britney-esque way of drawing media attention. Thankfully, serious research on neurobiological correlates of intelligence does not.  A recent paper from a highly regarded research team from UCLA adds more to the complex mystery of intelligence. From their paper, Luders and company found that “positive associations between intelligence and posterior callosal thickness may reflect a more efficient inter-hemispheric information transfer, positively affecting information processing and integration, and thus intellectual performance”. For geneticists and media hounds as well, I’d recommend to study this paper and others in this field very carefully as there are many neuroanatomical and physiological correlates. The genetics may similarly be a thicket of developmental pathways, not to mention a good night’s sleep, an apple a day, and parents who help you with your homework.

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